Q：Wise，how can I do ?

[tang]

Dear Dr. Wise,

Thank you for taking the time to read my post here.

I have known you and your research for many years. I even translated the posts of what you wrote about the clinical trial into Chinese and posted them on the Internet, which have gotten some attention. I hope there will be more people to pay attention to you and support your research. Some of them probably provide some help to you. Of course, it may also bring you some trouble, such as me and my questions.

I suffered a spinal cord injury-T3 complete in a car accident in the Chinese New Year of 2007. I survived the accident, but was paralyzed from the chest down.

My chest x-ray films which I had before show that the section of spinal burst fracture almost does not exist. The bones above and below the injury site are not in a straight line. In addition, they did not remove all the fragments of bone from my spinal cord according to the doctors. Is there any space at the site of injury for spinal cord to survive? How can I do?

I know the conclusion can only be made when you view my MRI. But I do not have MRI scans now due to interference from metallic instrumentation in my leg. By the way, I also broke my left leg in that accident. I underwent two operations for that leg, but the broken bones in that leg haven’t knitted together yet.

If we find the cure for SCI, is it necessary for me to do another operation to redress my distorted spine? I don't know how I can do. Give me some advice, will you? Thank you.

Finally, thank you and your colleagues again for all your efforts and commitment. I know you are great. Do hope everything goes well. Good luck!

[Wise Young]

Tang, I am sorry that I did not see your post earlier. In e way that we transplant the cells, the spinal cord will be decompressed before the transplant. Wise.

Dear Dr. Wise,

Thank you for taking the time to read my post here.

I have known you and your research for many years. I even translated the posts of what you wrote about the clinical trial into Chinese and posted them on the Internet, which have gotten some attention. I hope there will be more people to pay attention to you and support your research. Some of them probably provide some help to you. Of course, it may also bring you some trouble, such as me and my questions.

I suffered a spinal cord injury-T3 complete in a car accident in the Chinese New Year of 2007. I survived the accident, but was paralyzed from the chest down.

My chest x-ray films which I had before show that the section of spinal burst fracture almost does not exist. The bones above and below the injury site are not in a straight line. In addition, they did not remove all the fragments of bone from my spinal cord according to the doctors. Is there any space at the site of injury for spinal cord to survive? How can I do?

I know the conclusion can only be made when you view my MRI. But I do not have MRI scans now due to interference from metallic instrumentation in my leg. By the way, I also broke my left leg in that accident. I underwent two operations for that leg, but the broken bones in that leg haven’t knitted together yet.

If we find the cure for SCI, is it necessary for me to do another operation to redress my distorted spine? I don't know how I can do. Give me some advice, will you? Thank you.

Finally, thank you and your colleagues again for all your efforts and commitment. I know you are great. Do hope everything goes well. Good luck!

[tang]

Tang, I am sorry that I did not see your post earlier. In e way that we transplant the cells, the spinal cord will be decompressed before the transplant. Wise.

Dr.Wise,
Thank you for your response to my question. And thanks again for updating people here about progress in the trials.

[Wise Young]

Some people think we should not combine decompression and untethering procedures with cell transplantation in clinical trials, thinking that this does not allow us to distinguish between the effects of the decompression/untethering versus cell transplants. However, I believe that it would be unethical not to decompress and untether the spinal cord when you have the spinal cord exposed and see adhesions and something pressing of the cord. We know that compression and tethering is not good for the cord. It would be wrong to leave it and just transplant the cells, just to prove that the cells work.

Let's look at all the logical outcomes. If we are worried that the beneficial effects of the procedure comes from decompression and untethering and not from the cell transplant, the brute force way to test this in a trial is to have one group of patients who would just get the surgery and another group that would get the surgery and transplant. Unfortunately, unless you have a situation where the surgery is being done for some other reasons besides transplanting the cells, it will be very hard to recruit patients to a study where you do the surgery but do not transplant the cells.

So, in ChinaSCINet, we are using two ways to assess the effects of surgery alone. First, in the phase 2 trial, we are assessing the safety and efficacy of increasing doses of umbilical cord blood mononuclear cells. We are comparing five groups of patients, receiving 1.6, 3.2, 6.4 million cells and then 6.4 million cells plus methylprednisolone, and then 6.4 million cells plus methylprednisolone plus lithium. We did not know which was the safest and most effective dose. All the subjects had surgery where the spinal cord was exposed and any adhesion or compression of the cord was removed and corrected. If the beneficial effects were due to the surgery alone, all the subjects should show similar benefits. If the beneficial effects are related to cell dose, we should see increasing benefit with increasing dose. If there was any damage to the spinal cord during the procedure and methylprednisolone prevented or protected this, we should see better results in the subjects that received methylprednisolone. Finally, if lithium really helped increase regeneration and growth of the spinal cord, we should see the final group show the most benefit.

The second way that we are assessing the effects of surgery is because of a discovery by the Kunming group that subacute intradural decompression of the spinal cord is beneficial for recovery of function. They found nearly 50% of ASIA A (complete) spinal cord injury patients recover unassisted locomotion after subdural decompression at 2 days to 20 days after injury. They are now routinely doing this procedure in the patients. We are conducting a trial where they are comparing surgery only, surgery plus lithium, surgery plus cell transplant, and surgery plus cell transplant plus lithium. All the patients are getting the 6:6:6 walking program. If surgery alone is responsible for the beneficial effects, we should see no added benefit from the cell transplant. If lithium is beneficial, we should see improved recovery in the two groups that received lithium. Finally, if umbilical cord blood mononuclear cells is beneficial, we should see improved recovery in the two groups that received the transplants. Finally, if lithium and transplants are synergistic we should see the best recovery in both traetment groups.

In the phase 3 trial in China, I am considering proposing transplantion of the cells to all the subjects, randomizing them to lithium or placebo, and then randomizing them to intensive locomotor training or not. All the patients will be receiving surgery and therefore any decompression or adhesions at the injury site will be removed. Some of the subjects may get intensive locomotor training (not all our centers will have this option available) and I am thinking that we should send a subgroup of patients to Kunming for 3 months for the intensive locomotor training. Such a trial may have six possible outcomes.

1. Neither treatment group shows neurological improvement with or without locomotor training. We would conclude that umbilical cord blood mononuclear cell (UCBMC) transplants with or without lithium are ineffective. We would recommend against both UCBMC and lithium.

2. Neither treatment groups shows neurological improvement without locomotor training but both groups show neurological improvement with locomotor training. We would conclude that locomotor training is necessary and possibly sufficient for neurological improvement.

3. Both groups show similar neurological improvement with or without locomotor training. We would conclude that locomotor training is not necessary for recovery, that lithium is not necessary for recovery, and that UCBMC transplants or surgery may be sufficeint for recovery.

5. Both groups show similar neurological improvement with locomotor training but not without locomotor training. We would conclude that locomotor training is necessary, that UCBMC transplant or surgery are beneficial, and that lithium is not synergistic with UCBMC transplants.

6. The UCBMC transplants plus lithium group shows significantly more neurological improvement than UCBMC alone and only with locomotor recovery. We would conclude that UCBMC plus lithium is beneficial, that lithium is synergistic with UCBMC, and that locomotor training is important for improving recovery.

There are of course other possible outcomes but even with those that have been identified so far, the trial has the potential to give us a great deal of interesting information. I think that the data from the two phase 2 trials and the phase 3 trials will give us enough data to argue convincingly that surgery alone is or is not beneficial.

Wise.

[tang]

Dr.Wise,
I am very grateful to you for giving us such a detailed explanation. You are always so patient, kind and thoughtful. This is worthy of respect. But, you know, not every doctor is an ethical person and competent, so the procedure has a great risk, doesn’t it? By the way, have you missed a possible outcome among the six?

[Wise Young]

Dr.Wise,
I am very grateful to you for giving us such a detailed explanation. You are always so patient, kind and thoughtful. This is worthy of respect. But, you know, not every doctor is an ethical person and competent, so the procedure has a great risk, doesn’t it? By the way, have you missed a possible outcome among the six?

You are welcome. If we are asking people to risk their bodies to determine whether treatments are safe and effective, the least I can do is to explain the options and rationale. The procedure that we are talking about is not so risky but we need to find out how effective it is. If it works, that would be great and we will do our best to get it approved by the regulatory authorities. If it doesn't work, we will say so and go on to other therapies.

Regarding ethics, I gave a talk about clinical trial ethics at the recent Xi'an meeting in May. I said to the audience that charging for experimental therapies is not unethical. It presents a significant conflict of interest. A doctor who is making money from a treatment will have a difficult time saying that the treatment does not work.

Regarding competence, I think that the procedure is not so difficult and that most experienced surgeons can do a laminectomy and cut the dura to expose the spinal cord. In fact, I think many Chinese spinal surgeons are more experienced than most American surgeons and may be able to do the procedure better and faster.

Finally, I did not cover some of the more unlikely outcomes.

Wise.

[tang]

Thanks for your reply, Dr. Wise!